The purpose of this project is to elucidate the molecular pathogenesis of squamous cell neoplasms of the upper aerodigestive tract, and to enable the development of approaches for molecular therapy for these disorders. Human and murine squamous cell carcinoma cell line models have been developed and used to identify genes that are differentially expressed with tumor progression using molecular and immune assays. Proinflammatory cytokines, related signal transduction pathway molecules, and immediate early transcription factor genes have been shown to be overexpressed or activated with tumor progression, and are associated with aggressive growth and metastasis. A longitudinal study of serum cytokine factors as markers of response and survival was reported. The function of candidate genes identified by microarray have been examined following overexpression or inhibition by transfection of tumors with dominant negative constructs or RNAi has been the subject of recent investigations to identify potential targets for molecular therapy. The role of Egr-1 transcription factor in Hepatocyte Growth Factor-induced expression of angiogenic factors PDGF and VEGF has been elucidated. Hepatocyte Growth Factor/ MET receptor, Epidermal Growth Factor Receptor and the IL-6 Receptor have been identified as upstream activators of important signal pathways and gene programs. Identification of the role of NF-kB has led to a clinical study of a proteasome inhibitor which inhibits tumor growth and angiogenesis and sensitizes head and neck cancers to radiation. A study of the molecular effects of the drug on NF-kB and target genes and clinical toxicity and response was reported.